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Clinical Trial
. 2023 Sep:75:101762.
doi: 10.1016/j.molmet.2023.101762. Epub 2023 Jun 24.

Discovery of ecnoglutide - A novel, long-acting, cAMP-biased glucagon-like peptide-1 (GLP-1) analog

Wanjun Guo  1 , Zheng Xu  2 , Haixia Zou  1 , Feng Li  2 , Yao Li  1 , Jing Feng  1 , Zhiyi Zhu  1 , Qing Zheng  1 , Rui Zhu  1 , Bin Wang  1 , Yan Li  1 , Sujuan Hao  1 , Hong Qin  1 , Catherine L Jones  3 , Eric Adegbite  3 , Libnir Telusca  3 , Martijn Fenaux  3 , Weidong Zhong  3 , Mohammed K Junaidi  3 , Susan Xu  3 , Hai Pan  4
Affiliations
Clinical Trial

Discovery of ecnoglutide - A novel, long-acting, cAMP-biased glucagon-like peptide-1 (GLP-1) analog

Wanjun Guo et al. Mol Metab. 2023 Sep.

Abstract

Objective: Glucagon-like peptide (GLP)-1 is an incretin hormone that acts after food intake to stimulate insulin production, enhance satiety, and promote weight loss. Here we describe the discovery and characterization of ecnoglutide (XW003), a novel GLP-1 analog.

Methods: We engineered a series of GLP-1 peptide analogs with an alanine to valine substitution (Ala8Val) and a γGlu-2xAEEA linked C18 diacid fatty acid at various positions. Ecnoglutide was selected and characterized in GLP-1 receptor signaling assays in vitro, as well as in db/db mice and a diet induced obese (DIO) rat model. A Phase 1, double-blind, randomized, placebo-controlled, single (SAD) and multiple ascending dose (MAD) study was conducted to evaluate the safety, tolerability, and pharmacokinetics of subcutaneous ecnoglutide injection in healthy participants. SAD doses ranged from 0.03 to 1.0 mg; MAD doses ranged from 0.2 to 0.6 mg once weekly for 6 weeks (ClinicalTrials.gov Identifier: NCT04389775).

Results: In vitro, ecnoglutide potently induced cAMP (EC50 = 0.018 nM) but not GLP-1 receptor internalization (EC50 > 10 μM), suggesting a desirable signaling bias. In rodent models, ecnoglutide significantly reduced blood glucose, promoted insulin induction, and led to more pronounced body weight reduction compared to semaglutide. In a Phase 1 trial, ecnoglutide was generally safe and well tolerated as a once-weekly injection for up to 6 weeks. Adverse events included decreased appetite, nausea, and headache. The half-life at steady state ranged from 124 to 138 h, supporting once-weekly dosing.

Conclusions: Ecnoglutide showed a favorable potency, pharmacokinetic, and tolerability profile, as well as a simplified manufacturing process. These results support the continued development of ecnoglutide for the treatment of type 2 diabetes and obesity.

Keywords: Ecnoglutide; Glucagon-like peptide-1; Obesity; Peptide analog; Phase 1; Type 2 diabetes; XW003.

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Conflict of interest statement

Declaration of competing interest WG, HZ, YL, JF, ZZ, QZ, RZ, BW, YL, SH, HQ, CLJ, EA, LT, MF, WZ, MKJ, SX, and HP are, or were at the time the work was conducted, employees of Sciwind Biosciences.

Figures

Figure 1
Figure 1
Schematic of GLP-1 peptide analogs. GLP-1 peptide is shown with lysine (K) at variable positions. Linker of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) and γ-glutamic acid connects the peptide lysine to C18 diacid fatty acid. Figure was created with Biorender.com.
Figure 2
Figure 2
GLP-1 receptor signaling pathways induced by GLP-1 peptide analogs. DiscoverX Cell Signaling Assays were used to evaluate GLP-1 analogs for (A) cAMP induction in HitHunter hGLP1R-CHO-K1 cells (B) β-arrestin recruitment in PathHunter β-Arrestin hGLP1R-CHO-K1 cells and (C) β-arrestin-mediated GLP-1 receptor internalization in PathHunter Activated GPCR Internalization hGLP1R-U2OS cells. Percent activity was determined from the chemiluminescent readout of the assays. Mean and standard deviation are plotted.
Figure 3
Figure 3
Glucose and insulin response in db/db mice treated with GLP-1 analogs. (A and B) Single subcutaneous dose of GLP-1 analogs in db/db mice. Dosing is at time 0 h. (C) GLP-1 analogs were dosed subcutaneously daily for 42 days. Insulin was measured on Day 43. Significance was calculated for M4 vs semaglutide using a mixed models for repeated measures (MMRM) analysis (A and B), and for M4 vs vehicle and semaglutide using one-way ANOVA (C). ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, ∗∗∗∗p < 0.0001. M4, ecnoglutide. Mean and standard deviation (SD) are plotted.
Figure 4
Figure 4
Body weight response in db/db mice and DIO SD rats treated with GLP-1 analogs. (A–C) Male db/db mice administered vehicle, ecnoglutide (M4), or semaglutide by s.c. injection once daily for 42 days. (D) Male DIO SD rats dosed with vehicle, ecnoglutide (M4, 0.025 mg/kg), or semaglutide (0.025 mg/kg) s.c. once daily for 21 days, after which the active treatment groups were switched to dosing with the other compound for 7 days. Grey box indicates switched treatment period. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, ∗∗∗∗p < 0.0001. Mean and SD are plotted for B–D.
Figure 5
Figure 5
Gastrointestinal stability of ecnoglutide. Stability of ecnoglutide (M4) and semaglutide in pepsin at various pH levels. Mean and SD are plotted.
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